# CDK4/6 Inhibitors Suppress RB-Null Triple-Negative Breast Cancer by Inhibiting Mutant P53 Expression via RBM38 RNA-Binding Protein

## TL;DR

CDK4/6 inhibitors can suppress the growth of triple-negative breast cancer cells by reducing mutant p53 levels through an RNA-binding protein called RBM38.

## Contribution

The study reveals a novel mechanism by which CDK4/6 inhibitors suppress mutant p53 expression via RBM38 in RB-deficient and RB-proficient TNBC cells.

## Key findings

- CDK4/6 inhibitors reduce mutant p53 expression in both RB-proficient and RB-deficient TNBC cells.
- RBM38 dephosphorylation at serine 195 by CDK4/6 inhibitors inhibits mutant p53 mRNA translation.
- Mutant p53 may serve as a predictive biomarker for CDK4/6 inhibitor sensitivity in TNBC.

## Abstract

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, which are designed for targeting retinoblastoma (RB) protein phosphorylation and thereby block cancer cell growth, have been approved by the FDA as frontline targeted therapies for hormone receptor-positive (HR+), HER2-negative breast cancer. This study explores the potential application of CDK4/6 inhibitors in RB-deficient tumors. Indeed, we found that CDK4/6 inhibitors reduce mutant p53 expression and subsequently suppress tumor cell proliferation in both RB-proficient and RB-deficient triple-negative breast cancer (TNBC) cells. We also found that this effect is mediated by the RNA-binding protein RBM38, which is dephosphorylated at serine 195 by CDK4/6 inhibitors, resulting in the inhibition of mutant p53 mRNA translation. Collectively, our findings suggest that mutant p53 may serve as a predictive biomarker for CDK4/6 inhibitor sensitivity in TNBC and potentially other cancers harboring mutant p53.

Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have been developed and clinically used as a frontline targeted therapeutic agent for hormone receptor-positive (HR+), HER2-negative breast cancer. However, the efficacy for CDK4/6 inhibitors varies in different types of cancer and thus there is a need to identify new biomarkers that would help predict efficacy and/or resistance. Methods: We examined the effect of CDK4/6 inhibitors in both RB-proficient and -deficient triple-negative breast cancer (TNBC) cells. We also examined whether mutant p53 could be a target and/or prognostic marker for CDK4/6 inhibitors in (TNBC). Results: We found that CDK4/6 inhibitors suppress mutant p53 expression in both RB-proficient and RB-deficient TNBC cells. We also found that suppression of mutant p53 is responsible for CDK4/6 inhibitors suppressing TNBC cell survival. Mechanistically, we showed that CDK4/6 inhibitors suppress mutant p53 mRNA translation through the RNA-binding protein RBM38. Previously, we showed that when phosphorylated at serine 195, phosphorylated RBM38 interacts with eIF4G on p53 mRNA and promotes p53 mRNA translation. Indeed, we found that CDK4 phosphorylates RBM38 at serine 195, which subsequently enhances mutant p53 mRNA translation. Conclusions: Collectively, our findings suggest that mutant p53 could serve as a potential biomarker for the therapeutic efficacy of CDK4/6 inhibitors.